Work this year focused on an analysis of the effects of various[unreadable] changes in the specification of gap costs on the retrieval[unreadable] accuracy of protein profile search algorithms, with a view[unreadable] towards improving the retrieval accuracy of PSI-BLAST.[unreadable] [unreadable] In brief, the introduction of position-specific substitution[unreadable] costs has greatly improved the sensitivity of protein sequence[unreadable] database search programs: PSI-BLAST and related Hidden Markov[unreadable] Model (HMM) programs are able to recognize much more distant[unreadable] sequence relationships than can BLAST. HMM programs may employ[unreadable] position-specific gap costs as well. By modifying these programs,[unreadable] we found no improvement from position-specific gap costs that[unreadable] took account of the specific amino acids that were inserted or[unreadable] deleted. However, we did find a significant improvement from[unreadable] gap costs that varied according to their location.[unreadable] [unreadable] Incorporating position-specific gap costs into PSI-BLAST requires[unreadable] an accurate description of PSI-BLAST statistics under their use.[unreadable] The most promising path to this goal is the adaptation of the[unreadable] hybrid alignment scoring method for use with PSI-BLAST.